Distinct kinetics and dynamics of cross-presentation in liver sinusoidal endothelial cells compared to dendritic cells

Schurich, Anna; Böttcher, Jan; Burgdorf, Sven; Penzler, Patrick; Hegenbarth, Silke; Kern, Michaela; Dolf, Andreas; Endl, Elmar; Schultze, Joachim L.; Wiertz, Emmanuel J. H. J.; Stabenow, Dirk; Kurts, Christian; Knolle, Percy A.

doi:10.1002/hep.23075

Cited by 74 publications

(53 citation statements)

References 35 publications

(56 reference statements)

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“…4) showing OVA colocalization with the clathrin H chain in LECs at early times after exposure. Similar observations were made with LSECs (14) and are consistent with early endosome colocalization observed in BMDCs (46). At later time points, OVA was found in LAMP-1 + vesicles, supporting the data showing chloroquine inhibition of Ag cross-presentation (Supplemental Fig.…”

Section: Discussionsupporting

confidence: 89%

“…As described for other murine stromal cells, such as LSECs (14,48), aortic endothelial cells (49), and thymic stromal cells (50), we found that the TAP1-dependent transport of cytoplasmic peptides into the ER (Fig. 2D) and ER-golgi trafficking (Fig.…”

Section: Discussionsupporting

confidence: 83%

“…Although so-called "professional" APCs, such as CD8a + DCs, can process exogenous Ags for cross-presentation to CD8 + T cells, some nonhematopoietic cell types also were shown to be capable of cross-presentation (13). For example, liver sinusoidal endothelial cells (LSECs) are thought to capture and cross-present circulating Ag to CD8 + T cells, leading to CD8 + T cell deletion and the establishment of a tolerogenic environment (14). This is especially important in the liver, where LSECs are among the first cells to encounter the large diversity of foreign Ags from food, as well as TLR agonists from commensal sources (15).…”

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confidence: 99%

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Steady-State Antigen Scavenging, Cross-Presentation, and CD8+ T Cell Priming: A New Role for Lymphatic Endothelial Cells

Hirosue

Vokali

Raghavan

et al. 2014

The Journal of Immunology

179

189

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Until recently, the known roles of lymphatic endothelial cells (LECs) in immune modulation were limited to directing immune cell trafficking and passively transporting peripheral Ags to lymph nodes. Recent studies demonstrated that LECs can directly suppress dendritic cell maturation and present peripheral tissue and tumor Ags for autoreactive T cell deletion. We asked whether LECs play a constitutive role in T cell deletion under homeostatic conditions. In this study, we demonstrate that murine LECs under noninflamed conditions actively scavenge and cross-present foreign exogenous Ags to cognate CD8+ T cells. This cross-presentation was sensitive to inhibitors of lysosomal acidification and endoplasmic reticulum–golgi transport and was TAP1 dependent. Furthermore, LECs upregulated MHC class I and the PD-1 ligand PD-L1, but not the costimulatory molecules CD40, CD80, or CD86, upon Ag-specific interactions with CD8+ T cells. Finally, Ag-specific CD8+ T cells that were activated by LECs underwent proliferation, with early-generation apoptosis and dysfunctionally activated phenotypes that could not be reversed by exogenous IL-2. These findings help to establish LECs as APCs that are capable of scavenging and cross-presenting exogenous Ags, in turn causing dysfunctional activation of CD8+ T cells under homeostatic conditions. Thus, we suggest that steady-state lymphatic drainage may contribute to peripheral tolerance by delivering self-Ags to lymph node–resident leukocytes, as well as by providing constant exposure of draining peripheral Ags to LECs, which maintain tolerogenic cross-presentation of such Ags.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 83%

mentioning

confidence: 99%

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Steady-State Antigen Scavenging, Cross-Presentation, and CD8+ T Cell Priming: A New Role for Lymphatic Endothelial Cells

Hirosue

Vokali

Raghavan

et al. 2014

The Journal of Immunology

179

189

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“…Despite this, our experiments impressively demonstrate that a single tail vein injection of mCD105-LV Epo was sufficient to increase erythropoietin levels in the circulation to 25-fold above physiological values. Importantly, dose-response analysis revealed no toxicity in treated animals, and liver enzyme values remained unchanged even at a particle dose (15 mg p24), similar to that which substantially raised liver transaminase levels for VSV-G-LV (25 mg p24) 43 (supplemental Figure 5). These and the resulting high hematocrit values remained constant over several weeks in immunocompetent mice also, indicating that no cellular immune response against the transduced cells was mounted.…”

Section: Discussionmentioning

confidence: 55%

Specific gene delivery to liver sinusoidal and artery endothelial cells

Abel

Filali²,

Waern

et al. 2013

Blood

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Key Points• CD105-mediated cell entry using targeted lentiviral vectors leads to specific gene transfer of LSEC upon systemic administration.Different types of endothelial cells (EC) fulfill distinct tasks depending on their microenvironment. ECs are therefore difficult to genetically manipulate ex vivo for functional studies or gene therapy. We assessed lentiviral vectors (LVs) targeted to the EC surface marker CD105 for in vivo gene delivery. The mouse CD105-specific vector, mCD105-LV, transduced only CD105-positive cells in primary liver cell cultures. Upon systemic injection, strong reporter gene expression was detected in liver where mCD105-LV specifically transduced liver sinusoidal ECs (LSECs) but not Kupffer cells, which were mainly transduced by nontargeted LVs. Tumor ECs were specifically targeted upon intratumoral vector injection. Delivery of the erythropoietin gene with mCD105-LV resulted in substantially increased erythropoietin and hematocrit levels. The human CD105-specific vector (huCD105-LV) transduced exclusively human LSECs in mice transplanted with human liver ECs. Interestingly, when applied at higher dose and in absence of target cells in the liver, huCD105-LV transduced ECs of a human artery transplanted into the descending mouse aorta. The data demonstrate for the first time targeted gene delivery to specialized ECs upon systemic vector administration. This strategy offers novel options to better understand the physiological functions of ECs and to treat genetic diseases such as those affecting blood factors. (Blood. 2013;122(12):2030-2038

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“…This led us to investigate whether the numbers of peptideloaded MHC-I molecules and thus the strength of TCR signaling influenced tolerogenic T cell priming by cross-presenting LSECs. LSECs represent a unique liver-resident cell population that is even more potent in cross-presentation than CD8a + splenic DCs when compared at a per-cell basis (19). Cross-presentation of soluble Ag by LSECs in vivo is functional and sufficient to cause Ag-specific retention of circulating naive CD8 T cells to the liver (5).…”

Section: Discussionmentioning

confidence: 99%

Dynamic Regulation of CD8 T Cell Tolerance Induction by Liver Sinusoidal Endothelial Cells

Schurich

Berg

Stabenow

et al. 2010

The Journal of Immunology

Self Cite

111

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Cross-presentation of soluble Ag on MHC class I molecules to naive CD8 T cells by liver sinusoidal endothelial cells (LSECs) leads to induction of T cell tolerance that requires interaction between coinhibitory B7-H1 on LSECs and programmed cell death-1 on CD8 T cells. In this study, we investigate whether cross-presentation of high as well as low Ag concentrations allowed for LSEC-induced tolerance. Ag concentration directly correlated with the cross-presentation capacity of murine LSECs and thus strength of TCR stimulation. Although LSEC cross-presentation at low-Ag concentrations resulted in tolerance, they induced differentiation into effector T cells (CTL) at high-Ag concentrations. CTL differentiation under these conditions was not caused by increased expression of costimulatory CD80/86 on cross-presenting LSECs but was determined by early IL-2 release from naive CD8 T cells. B7-H1 signals from LSECs and TCR avidity reciprocally controlled early T cell release of IL-2 and CTL differentiation. B7-H1 expression directly correlated with cross-presentation at low- but not high-Ag concentrations, indicating an imbalance between TCR and coinhibitory signals regulating T cell release of IL-2. Exogenous IL-2 overrode coinhibitory B7-H1–mediated signals by LSECs and induced full CTL differentiation. Our results imply that LSEC-mediated T cell tolerance can be broken in situations where T cells bearing high-avidity TCR encounter LSECs cross-presenting high numbers of cognate MHC class I peptide molecules, such as during viral infection of the liver. Furthermore, we attribute a novel costimulatory function to IL-2 acting in a T cell autonomous fashion to promote local induction of immunity in the liver even in the absence of CD80/86 costimulation.

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Distinct kinetics and dynamics of cross-presentation in liver sinusoidal endothelial cells compared to dendritic cells

Cited by 74 publications

References 35 publications

Steady-State Antigen Scavenging, Cross-Presentation, and CD8+ T Cell Priming: A New Role for Lymphatic Endothelial Cells

Steady-State Antigen Scavenging, Cross-Presentation, and CD8+ T Cell Priming: A New Role for Lymphatic Endothelial Cells

Specific gene delivery to liver sinusoidal and artery endothelial cells

Dynamic Regulation of CD8 T Cell Tolerance Induction by Liver Sinusoidal Endothelial Cells

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